Hydroxamic acid compounds and methods of use thereof

ABSTRACT

The present invention relates to a novel class of hydroxamic acid derivatives having at least two aryl containing groups, at least one of which is a quinolinyl, isoquinolinyl or benzyl moiety, linked to the hydroxamic acid group through a methylene chain. The hydroxamic acid compounds can be used to treat cancer, for example, brain cancer. The hydroxamic acid compounds can also inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention are also useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases.

RELATED APPLICATION

[0001] This application claims the benefit of U.S. Application Ser. No.60/459,826, filed Apr. 1, 2003, the contents of which are herebyincorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

[0002] Compounds having a hydroxamic acid moiety have been shown topossess useful biological activities. For example, many peptidylcompounds possessing a hydroxamic acid moiety are known to inhibitmatrix metalloproteinases (MMPs) which are a family of zincendopeptidases. The MMPs play a key role in both physiological andpathological tissue degradation. Therefore, peptidyl compounds whichhave the ability to inhibit the action of MMPs, show utility for thetreatment or prophylaxis of conditions involving tissue breakdown andinflammation. Further, compounds having a hydroxamic acid moiety havebeen shown to inhibit histone deacetylases (HDACs), based at least inpart on the zinc binding property of the hydroxamic acid group. Theinhibition of HDACs can repress gene expression, including expression ofgenes related to tumor suppression. Inhibition of histone deacetylasecan lead to the histone-deacetylase-mediated transcriptional repressionof tumor suppressor genes. For example, inhibition of histonedeacetylase can provide a method for treating cancer, hematologicaldisorders, such as hematopoiesis, and genetic related metabolicdisorders.

[0003] More specifically, transcriptional regulation is a major event incell differentiation, proliferation, and apoptosis. There are severallines of evidence that histone acetylation and deacetylation aremechanisms by which transcriptional regulation in a cell is achieved(Grunstein, M., Nature, 389: 349-52 (1997) ). These effects are thoughtto occur through changes in the structure of chromatin by altering theaffinity of histone proteins for coiled DNA in the nucleosome. There arefive types of histones that have been identified. Histones H2A, H2B, H3and H4 are fouond in the nucleosome and H1 is a linker located betweennucleosomes. Each nucleosome contains two of each histone type withinits core, except for HI, which is present singly in the outer portion ofthe nucleosome structure. It is believed that when the histone proteinsare hypoacetylated, there is a greater affinity of the histone to theDNA phosphate backbone. This affinity causes DNA to be tightly bound tothe histone and renders the DNA inaccessible to transcriptionalregulatory elements and machinery. The regulation of acetylated statesoccurs through the balance of activity between two enzyme complexes,histone acetyl transferase (HAT) and histone deacetylase (HDAC). Thehypoacetylated state is thought to inhibit transcription of associatedDNA. This hypoacetylated state is catalyzed by large multiproteincomplexes that include HDAC enzymes. In particular, HDACs have beenshown to catalyze the removal of acetyl groups from the chromatin corehistones.

[0004] It has been shown in several instances that the disruption of HATor HDAC activity is implicated in the development of a malignantphenotype. For instance, in acute promyelocytic leukemia, theoncoprotein produced by the fusion of PML and RAR alpha appears tosuppress specific gene transcription through the recruitment of HDACs(Lin, R. J. et al., Nature 391:811-14 (1998) ). In this manner, theneoplastic cell is unable to complete differentiation and leads toexcess proliferation of the leukemic cell line.

[0005] U.S. Pat. No. 5,369,108, 5,932,616, 5,700,811, 6,087,367 and6,511, 990, the contents of which are hereby incorporated by reference,disclose hydroxamic acid derivatives useful for selectively inducingterminal differentiation, cell growth arrest or apoptosis of neoplasticcells. In addition to their biological activity as antitumor agents,these hydroxamic acid derivatives have recently been identified asuseful for treating or preventing a wide variety of thioredoxin(TRX)-mediated diseases and conditions, such as inflammatory diseases,allergic diseases, autoimmune diseases, diseases associated withoxidative stress or diseases characterized by cellularhyperproliferation (U.S. application Ser. No. 10/369,094, filed Feb. 15,2003, the entire content of which is hereby incorporated by reference).Further, these hydroxamic acid derivatives have been identified asuseful for treating diseases of the central nervous system (CNS) such asneurodegenerative diseases and for treating brain cancer (See, U.S.application Ser. No. 10/273,401, filed Oct. 16, 2002, the entire contentof which is hereby incorporated by reference).

[0006] The inhibition of HDAC by the hydroxamic acid containing compoundsuberoylanilide hydroxamic acid (SAHA) disclosed in the above referencedU.S. Patents, is thought to occur through direct interaction with thecatalytic site of the enzyme as demonstrated by X-ray crystallographystudies (Finnin, M. S. et al., Nature 401:188-193 (1999)). The result ofHDAC inhibition is not believed to have a generalized effect on thegenome, but rather, only affects a small subset of the genome (Van Lint,C. et al., Gene Expression 5:245-53 (1996)). Evidence provided by DNAmicroarrays using malignant cell lines cultured with a HDAC inhibitorshows that there are a finite (1-2%) number of genes whose products arealtered. For example, cells treated in culture with HDAC inhibitors showa consistent induction of the cyclin-dependent kinase inhibitor p21(Archer, S. Shufen, M. Shei, A., Hodin, R. PNAS 95:6791-96 (1998)). Thisprotein plays an important role in cell cycle arrest. HDAC inhibitorsare thought to increase the rate of transcription of p21 by propagatingthe hyperacetylated state of histones in the region of the p21 gene,thereby making the gene accessible to transcriptional machinery. Geneswhose expression is not affected by HDAC inhibitors do not displaychanges in the acetylation of regional associated histones (Dressel, U.et al., Anticancer Research 20(2A): 1017-22 (2000)).

[0007] Further, hydroxamic acid derivatives such as SAHA have theability to induce tumor cell growth arrest, differentiation and/orapoptosis (Richon et al., Proc. Natl. Acad. Sci. USA, 93:5705-5708(1996)). These compounds are targeted towards mechanisms inherent to theability of a neoplastic cell to become malignant, as they do not appearto have toxicity in doses effective for inhibition of tumor growth inanimals (Cohen, L. A. et al., Anticncer Research 19:4999-5006 (1999)).

[0008] In view of the wide variety of applications for compoundscontaining hydroxamic acid moieties, the development of new hydroxamicacid derivatives having improved properties, for example, increasedpotency or increased bioavailability is highly desirable.

SUMMARY OF THE INVENTION

[0009] The present invention relates to a novel class of hydroxamic acidderivatives. In one embodiment, the hydroxamic acid derivatives caninhibit histone deacetylase and are suitable for use in selectivelyinducing terminal differentiation, and arresting cell growth and/orapoptosis of neoplastic cells, thereby inhibiting proliferation of suchcells. Thus, the compounds of the present are useful in treating cancerin a subject. The compounds of the invention are also useful in theprevention and treatment of TRX-mediated diseases, such as autoimmune,allergic and inflammatory diseases, and in the prevention and/ortreatment of diseases of the central nervous system (CNS), such asneurodegenerative diseases.

[0010] It has been unexpectedly and surprisingly discovered that certainhydroxamic acid derivatives having at least two aryl containing groups,at least one of which is a quinolinyl, isoquinolinyl or benzyl moiety,linked to the hydroxamic acid group through a methylene chain, showimproved activity as HDAC inhibitors.

[0011] The present invention relates to compounds represented byStructural Formula I and pharmaceutically acceptable salts, solvates andhydrates thereof:

[0012] In Structural Formula I, R₁ is a substituted or unsubstitutedaryl group, arylalkyl group, arylamino group, arylalkylamino group,aryloxy group or arylalkoxy group and n is an integer from 3 to 10.

[0013] In a particular embodiment, n is 5 for the compounds ofStructural Formula I.

[0014] In another embodiment, R₁ is a substituted or unsubstitutedheteroaryl group, phenyl group or naphthyl group for the compounds ofStructural Formula I.

[0015] In yet another embodiment, R₁ is a substituted or unsubstitutedpyridyl group, quinolinyl group or isoquinolinyl group for the compoundsof Structural Formula I.

[0016] In a further embodiment, R₁ is a substituted or unsubstitutedphenyl group for the compounds of Structural Formula I. In a particularembodiment, R₁ of Formula I is an unsubstituted phenyl group. In a moreparticular embodiment, R₁ of Formula I is an unsubstituted phenyl groupand n is 5.

[0017] In another embodiment, R₁ is an unsubstituted pyridyl group forthe compounds of Structural Formula I. In a particular embodiment, theunsubstituted pyridyl group is a β-pyridyl group. In a more particularembodiment, the unsubstituted pyridyl group is a β-pyridyl group and nis 5.

[0018] In yet another embodiment, R₁ is an unsubstituted quinolinylgroup for the compounds of Structural Formula I. In a particularembodiment, the unsubstituted quinolinyl group is a 2-quinolinyl group.In a more particular embodiment, the unsubstituted quinolinyl group is a2-quinolinyl group and n is 5.

[0019] In another embodiment, R₁ is a substituted or unsubstitutedarylalkyloxy group for the compounds of Structural Formula I. In aparticular embodiment, R₁ of Structural Formula I is a substituted orunsubstituted benzyloxy group. In a more particular embodiment, thebenzyloxy group is and unsubstitututed benzyloxy group. In an even moreparticular embodiment, the benzyloxy group is an unsubstituted benzyloxygroup and n is 5.

[0020] In a specific embodiment, the compound of Formula I isrepresented by the following structure:

[0021] In another specific embodiment, the compound of Formula I isrepresented by the following structure:

[0022] In yet another specific embodiment, the compound of Formula I isrepresented by the following structure:

[0023] In still another specific embodiment, the compound of Formula Iis represented by the following structure:

[0024] The present invention also relates to compounds of StructuralFormula II and pharmaceutically acceptable salts, solvates and hydratesthereof:

[0025] In Structural Formula II, Q₁ is a substituted or unsubstitutedquinolinyl or isoquinolinyl group and n is an integer from 3 to 10.

[0026] In one embodiment, Q₁ is an 8-quinolinyl group for the compoundsof Structural Formula II.

[0027] In another embodiment, the pyridyl group of Structural Formula IIis a β-pyridyl group. In a particular embodiment, wherein the pyridylgroup is a β-pyridyl group, Q₁ is an 8-quinolinyl group. In a moreparticular embodiment, the pyridyl group is a β-pyridyl group, Q₁ is an8-quinolinyl group and n is 5.

[0028] In a specific embodiment, the compound of Formula II isrepresented by the following structure:

[0029] The present invention further relates to compounds of StructuralFormula III and pharmaceutically acceptable salts, solvates and hydratesthereof:

[0030] In Structural Formula III, Q₁ and Q₂ are independently asubstituted or unsubstituted quinolinyl or isoquinolinyl group and n isan integer from 3 to 10.

[0031] In a particular embodiment, Q₁ is an 8-quinolinyl group.

[0032] In another embodiment, Q₂ is a 2-quinolinyl group. In aparticular embodiment, wherein Q₂ is a 2-quinolinyl group, Q₁ is an8-quinolinyl group. In a more particular embodiment, Q₂ is a2-quinolinyl group, Q₁ is an 8-quinolinyl group and n is 5.

[0033] In a specific embodiment, the compound of Formula III isrepresented by the following structure:

[0034] The present invention further relates to compounds of StructuralFormula IV and pharmaceutically acceptable salts, solvates and hydratesthereof:

[0035] In Structural Formula IV, R₁ is an arylalkyl, R₂ is a substitutedor unsubstituted aryl group, arylalkyl group, arylamino group,arylalkylamino group, aryloxy group or arylalkoxy group, A is an amideand n is an integer from 3 to 10.

[0036] In a particular embodiment, R₁ is a benzyl group for thecompounds of Structural Formula IV.

[0037] In another embodiment, R₁ is a benzyl group and R₂ is asubstituted or unsubstituted quinolinyl group for the compounds ofStructural Formula IV. In a particular embodiment, R₂ is anunsubstituted quinolinyl group. In an even more particular embodiment,the unsubstituted quinolinyl group is a 2-quinolinyl group. In a furtherembodiment, R₁ is a benzyl group, R₂ is a 2-quinolinyl group and n is 5.

[0038] In a specific embodiment, the compound of Formula IV isrepresented by the following structure:

[0039] In yet another embodiment, R₁ is a benzyl group and R₂ is asubstituted or unsubstituted benzyloxy group for the compounds ofStructural Formula IV. In a particular embodiment, R₂ is anunsubstituted benzyloxy group. In a further embodiment, R₁ is a benzylgroup, R₂ is an unsubstituted benzyloxy group and n is 5.

[0040] In a specific embodiment, the compound of Formula IV isrepresented by the following structure:

[0041] In still another embodiment, R₁ is a benzyl group and R₂ is asubstituted or unsubstituted phenyl group for the compounds ofStructural Formula IV. In a particular embodiment, R₂ is anunsubstituted phenyl group. In a further embodiment, R₁ is a benzylgroup, R₂ is an unsubstituted phenyl group and n is 5.

[0042] In a specific embodiment, the compound of Formula IV isrepresented by the following structure:

[0043] In another embodiment, R₁ is a benzyl group and R₂ is asubstituted or unsubstituted pyridyl group for the compounds ofStructural Formula IV. In a particular embodiment, R₂ is anunsubstituted pyridyl group. In an even more particular embodiment, theunsubstituted pyridyl group is a β-pyridyl. In a further embodiment, R₁is a benzyl group, R₂ is a β-pyridyl group and n is 5.

[0044] In a specific embodiment, the compound of Formula IV isrepresented by the following structure:

[0045] The invention also relates to a pharmaceutical compositioncomprising a therapeutically effective amount of any one of thehydroxamic acid compounds and a pharmaceutically acceptable carrier.

[0046] The invention further relates to use of the hydroxamic acidcompounds for the manufacture of a medicament for treating the diseasesand disorders described herein such as cancer, TRX-mediated diseases anddisorders and neurodegenerative diseases and disorders.

[0047] The invention also relates to method of using the hydroxamic acidderivatives described herein.

[0048] In a particular embodiment, the invention relates to a method oftreating cancer in a subject in need of treatment comprisingadministering to said subject a therapeutically effective amount of ahydroxamic acid derivative described herein.

[0049] In another embodiment, the method of use is a method ofselectively inducing terminal differentiation of neoplastic cells andthereby inhibiting proliferation of such cells. The method comprisescontacting the cells under suitable conditions with an effective amountof one or more of the hydroxamic acid compounds described herein.

[0050] In another embodiment, the hydroxamic acid derivatives are usedin a method of selectively inducing cell growth arrest of neoplasticcells and thereby inhibiting proliferation of such cells. The methodcomprises contacting the cells under suitable conditions with aneffective amount of one or more of the hydroxamic acid compoundsdescribed herein.

[0051] In yet another embodiment, the hydroxamic acid derivatives areused in a method of inducing terminal differentiation of tumor cells ina tumor comprising contacting the cells with an effective amount of anyone or more of the hydroxamic acid compounds described herein.

[0052] In still another embodiment, the hydroxamic acid derivatives areused in a method of inhibiting the activity of histone deacetylasecomprising contacting the histone deacetylase with an effective amountof one or more of the hydroxamic acid compounds described herein.

[0053] In another embodiment, the hydroxamic acid derivatives are usedin a method of treating a thioredoxin (TRX)-mediated disease or disorderin a subject in need thereof, comprising administering to the subject atherapeutically effective amount of one or more of the hydroxamic acidcompounds described herein.

[0054] In another embodiment, the hydroxamic acid derivatives are usedin a method of treating a disease of the central nervous system in asubject in need thereof comprising administering to the subject atherapeutically effective amount of any one or more of the hydroxamicacid compounds.

[0055] In particular embodiments, the CNS disease is a neurodegenerativedisease. In further embodiments, the neurogenerative disease is aninherited neurodegenerative disease, such as those inheritedneurodegenerative diseases which are polyglutamine expansion diseases.

[0056] The invention further relates to use of the compounds describedherein for the manufacture of a medicament for treating cancer (e.g.,brain cancer) and for treating thioredoxin (TRX)-mediated diseases.

[0057] The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0058] A description of preferred embodiments of the invention follows.

[0059] The present invention relates to a novel class of hydroxamic acidderivatives. In one embodiment, the hydroxamic acid derivatives caninhibit histone deacetylase and are suitable for use in selectivelyinducing terminal differentiation, and arresting cell growth and/orapoptosis of neoplastic cells, thereby inhibiting proliferation of suchcells. Thus, the compounds of the present are useful in treating cancera subject. The compounds of the invention are also useful in theprevention and treatment of TRX-mediated diseases, such as autoimmune,allergic and inflammatory diseases, and in the prevention and/ortreatment of diseases of the central nervous system (CNS), such asneurodegenerative diseases.

[0060] It has been unexpectedly and surprisingly discovered that certainhydroxamic acid derivatives having at least two aryl containing groups,at least one of which is a quinolinyl, isoquinolinyl or benzyl moiety,linked to the hydroxamic acid group through a methylene chain, showimproved activity as HDAC inhibitors.

[0061] Compounds

[0062] The present invention relates to compounds represented byStructural Formula I and pharmaceutically acceptable salts, solvates andhydrates thereof:

[0063] In Structural Formula I, R₁ is a substituted or unsubstitutedaryl group, arylalkyl group, arylamino group, arylalkylamino group,aryloxy group or arylalkoxy group and n is an integer from 3 to 10.

[0064] In a particular embodiment, n is 5 for the compounds ofStructural Formula I.

[0065] In another embodiment, R₁ is a substituted or unsubstitutedheteroaryl group, phenyl group or naphthyl group for the compounds ofStructural Formula I.

[0066] In yet another embodiment, R₁ is a substituted or unsubstitutedpyridyl group, quinolinyl group or isoquinolinyl group for the compoundsof Structural Formula I.

[0067] In a further embodiment, R₁ is a substituted or unsubstitutedphenyl group for the compounds of Structural Formula I. In a particularembodiment, R₁ of Formula I is an unsubstituted phenyl group. In a moreparticular embodiment, R₁ of Formula I is an unsubstituted phenyl groupand n is 5.

[0068] In another embodiment, R₁ is an unsubstituted pyridyl group forthe compounds of Structural Formula I. In a particular embodiment, theunsubstituted pyridyl group is a β-pyridyl group. In a more particularembodiment, the unsubstituted pyridyl group is a β-pyridyl group and nis 5.

[0069] In yet another embodiment, R₁ is an unsubstituted quinolinylgroup for the compounds of Structural Formula I. In a particularembodiment, the unsubstituted quinolinyl group is a 2-quinolinyl group.In a more particular embodiment, the unsubstituted quinolinyl group is a2-quinolinyl group and n is 5.

[0070] In another embodiment, R₁ is a substituted or unsubstitutedarylalkyloxy group for the compounds of Structural Formula I. In aparticular embodiment, R₁ of Structural Formula I is a substituted orunsubstituted benzyloxy group. In a more particular embodiment, thebenzyloxy group is and unsubstitututed benzyloxy group. In an even moreparticular embodiment, the benzyloxy group is an unsubstituted benzyloxygroup and n is 5.

[0071] In a specific embodiment, the compound of Formula I isrepresented by the following structure:

[0072] In another specific embodiment, the compound of Formula I isrepresented by the following structure:

[0073] In yet another specific embodiment, the compound of Formula I isrepresented by the following structure:

[0074] In still another specific embodiment, the compound of Formula Iis represented by the following structure:

[0075] The present invention also relates to compounds of StructuralFormula II and pharmaceutically acceptable salts, solvates and hydratesthereof:

[0076] In Structural Formula II, Q₁ is a substituted or unsubstitutedquinolinyl or isoquinolinyl group and n is an integer from 3 to 10.

[0077] In one embodiment, Q₁ is an 8-quinolinyl group for the compoundsof Structural Formula II.

[0078] In another embodiment, the pyridyl group of Structural Formula IIis a β-pyridyl group. In a particular embodiment, wherein the pyridylgroup is a β-pyridyl group, Q₁ is an 8-quinolinyl group. In a moreparticular embodiment, the pyridyl group is a β-pyridyl group, Q₁ is an8-quinolinyl group and n is 5.

[0079] In a specific embodiment, the compound of Formula II isrepresented by the following structure:

[0080] The present invention further relates to compounds of StructuralFormula III and pharmaceutically acceptable salts, solvates and hydratesthereof:

[0081] In Structural Formula III, Q₁ and Q₂ are independently asubstituted or unsubstituted quinolinyl or isoquinolinyl group and n isan integer from 3 to 10.

[0082] In a particular embodiment, Q₁ is an 8-quinolinyl group.

[0083] In another embodiment, Q₂ is a 2-quinolinyl group. In aparticular embodiment, wherein Q₂ is a 2-quinolinyl group, Q₁ is an8-quinolinyl group. In a more particular embodiment, Q₂ is a2-quinolinyl group, Q₁ is an 8-quinolinyl group and n is 5.

[0084] In a specific embodiment, the compound of Formula III isrepresented by the following structure:

[0085] The present invention further relates to compounds of StructuralFormula IV and pharmaceutically acceptable salts, solvates and hydratesthereof:

[0086] In Structural Formula IV, R₁ is an arylalkyl, R₂ is a substitutedor unsubstituted aryl group, arylalkyl group, arylamino group,arylalkylamino group, aryloxy group or arylalkoxy group, A is an amideand n is an integer from 3 to 10.

[0087] In a particular embodiment, R₁ is a benzyl group for thecompounds of Structural Formula IV.

[0088] In another embodiment, R₁ is a benzyl group and R₂ is asubstituted or unsubstituted quinolinyl group for the compounds ofStructural Formula IV. In a particular embodiment, R₂ is anunsubstituted quinolinyl group. In an even more particular embodiment,the unsubstituted quinolinyl group is a 2-quinolinyl group. In a furtherembodiment, R₁ is a benzyl group, R₂ is a 2-quinolinyl group and n is 5.

[0089] In a specific embodiment, the compound of Formula IV isrepresented by the following structure:

[0090] In yet another embodiment, R₁ is a benzyl group and R₂ is asubstituted or unsubstituted benzyloxy group for the compounds ofStructural Formula IV. In a particular embodiment, R₂ is anunsubstituted benzyloxy group. In a further embodiment, R₁ is a benzylgroup, R₂ is an unsubstituted benzyloxy group and n is 5.

[0091] In a specific embodiment, the compound of Formula IV isrepresented by the following structure:

[0092] In still another embodiment, R₁ is a benzyl group and R₂ is asubstituted or unsubstituted phenyl group for the compounds ofStructural Formula IV. In a particular embodiment, R₂ is anunsubstituted phenyl group. In a further embodiment, R₁ is a benzylgroup, R₂ is an unsubstituted phenyl group and n is 5.

[0093] In a specific embodiment, the compound of Formula IV isrepresented by the following structure:

[0094] In another embodiment, R₁ is a benzyl group and R₂ is asubstituted or unsubstituted pyridyl group for the compounds ofStructural Formula IV. In a particular embodiment, R₂ is anunsubstituted pyridyl group. In an even more particular embodiment, theunsubstituted pyridyl group is a β-pyridyl. In a further embodiment, R₁is a benzyl group, R₂ is a β-pyridyl group and n is 5.

[0095] In a specific embodiment, the compound of Formula IV isrepresented by the following structure:

[0096] The invention also relates to a pharmaceutical compositioncomprising a therapeutically effective amount of any one of thehydroxamic acid compounds and a pharmaceutically acceptable carrier.

[0097] An “aliphatic group” is non-aromatic, consists solely of carbonand hydrogen and can optionally contain one or more units ofunsaturation, e.g., double and/or triple bonds. An aliphatic group canbe straight chained, branched or cyclic. When straight chained orbranched, an aliphatic group typically contains between about 1 andabout 12 carbon atoms, more typically between about 1 and about 6 carbonatoms. When cyclic, an aliphatic group typically contains between about3 and about 10 carbon atoms, more typically between about 3 and about 7carbon atoms. Aliphatic groups are preferably C₁-C₁₂ straight chained orbranched alkyl groups (i.e., completely saturated aliphatic groups),more preferably C₁-C₆ straight chained or branched alkyl groups.Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyland tert-butyl.

[0098] An “aromatic group” (also referred to as an “aryl group”) as usedherein includes carbocyclic aromatic groups, heterocyclic aromaticgroups (also referred to as “heteroaryl”) and fused polycyclic aromaticring system as defined herein.

[0099] A “carbocyclic aromatic group” is an aromatic ring of 5 to 14carbons atoms, and includes a carbocyclic aromatic group fused with a5-or 6-membered cycloalkyl group such as indan. Examples of carbocyclicaromatic groups include, but are not limited to, phenyl, naphthyl, e.g.,1-naphthyl and 2-naphthyl; anthracenyl, e.g., 1-anthracenyl,2-anthracenyl; phenanthrenyl; fluorenonyl, e.g., 9-fluorenonyl, indanyland the like. A carbocyclic aromatic group is optionally substitutedwith a designated number of substituents, described below.

[0100] A “heterocyclic aromatic group” (or “heteroaryl”) is amonocyclic, bicyclic or tricyclic aromatic ring of 5- to 14-ring atomsof carbon and from one to four heteroatoms selected from O, N, or S.Examples of heteroaryl include, but are not limited to pyridyl, e.g.,2-pyridyl (also referred to as α-pyridyl), 3-pyridyl (also referred toas β-pyridyl) and 4-pyridyl (also referred to as γ-pyridyl); thienyl,e.g., 2-thienyl and 3-thienyl; furanyl, e.g., 2-furanyl and 3-furanyl;pyrimidyl, e.g., 2-pyrimidyl and 4-pyrimidyl; imidazolyl, e.g.,2-imidazolyl; pyranyl, e.g., 2-pyranyl and 3-pyranyl; pyrazolyl, e.g.,4-pyrazolyl and 5-pyrazolyl; thiazolyl, e.g., 2-thiazolyl, 4-thiazolyland 5-thiazolyl; thiadiazolyl; isothiazolyl; oxazolyl, e.g., 2-oxazoyl,4-oxazoyl and 5-oxazoyl; isoxazoyl; pyrrolyl; pyridazinyl; pyrazinyl andthe like. Heterocyclic aromatic (or heteroaryl) as defined above may beoptionally substituted with a designated number of substituents, asdescribed below for aromatic groups.

[0101] A “fused polycyclic aromatic” ring system is a carbocyclicaromatic group or heteroaryl fused with one or more other heteroaryl ornonaromatic heterocyclic ring. Examples include, quinolinyl andisoquinolinyl, e.g, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl,5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl,1-isoquinolinyl, 3-quinolinyl, 4-isoquinolinyl, 5-isoquinolinyl,6-isoquinolinyl, 7-isoquinolinyl and 8-isoquinolinyl; benzofuranyl e.g.,2-benzofuranyl and 3-benzofuranyl; dibenzofuranyl.e.g.,2,3-dihydrobenzofuranyl; dibenzothiophenyl; benzothienyl, e.g.,2-benzothienyl and 3-benzothienyl; indolyl, e.g., 2-indolyl and3-indolyl; benzothiazolyl, e.g., 2-benzothiazolyl; benzooxazolyl, e.g.,2-benzooxazolyl; benzimidazolyl, e.g., 2-benzoimidazolyl; isoindolyl,e.g., 1-isoindolyl and 3-isoindolyl; benzotriazolyl; purinyl;thianaphthenyl and the like. Fused polycyclic aromatic ring systems mayoptionally be substituted with a designated number of substituents, asdescribed herein.

[0102] An “aralkyl group” (arylalkyl) is an alkyl group substituted withan aromatic group, preferably a phenyl group. A preferred aralkyl groupis a benzyl group. Suitable aromatic groups are described herein andsuitable alkyl groups are described herein. Suitable substituents for anaralkyl group are described herein.

[0103] An “aryloxy group” is an aryl group that is attached to acompound via an oxygen (e.g., phenoxy).

[0104] An “alkoxy group, as used herein, is a straight chain or branchedc1-c12 or cyclic C₃-C₁₂ alkyl group that is connected to a comound viaan oxygen atom. Examples of alkoxy groups include but are not limited tomethoxy, ethoxy and propoxy.

[0105] An “arylalkoxy group” is an arylalkyl group that is attached to acompound via an oxygen on the alkyl portion of the arylalkyl (e.g.,phenylmethoxy).

[0106] An “arylamino group” as used herein, is an aryl group that isattached to a compound via a nitrogen.

[0107] As used herein, an “arylalkylamino group” is an arylalkyl groupthat is attached to a compound via a nitrogen on the alkyl portion ofthe arylalkyl.

[0108] As used herein, many moieties or groups are referred to as beingeither “substituted or unsubstituted”. When a moiety is referred to assubstituted, it denotes that any portion of the moiety that is known toone skilled in the art as being available for substitution can besubstituted. For example, the substitutable group can be a hydrogen atomwhich is replaced with a group other than hydrogen (i.e., a substituentgroup). Multiple substituent groups can be present. When multiplesubstituents are present, the substituents can be the same or differentand substitution can be at any of the substitutable sites on the ring.Such means for substitution are well-known in the art. For purposes ofexemplification, which should not be construed as limiting the scope ofthis invention, some examples of groups that are substituents are: alkylgroups (which can also be substituted, such as CF₃), alkoxy groups(which can be substituted, such as OCF₃), a halogen or halo group (F,Cl, Br, I), hydroxy, nitro, oxo, —CN, —COH, —COOH, amino, N-alkylaminoor N,N-dialkylamino (in which the alkyl groups can also be substituted),esters (—C(O)—OR, where R can be a group such as alkyl, aryl, etc.,which can be substituted), aryl (most preferred is phenyl, which can besubstituted) and arylalkyl (which can be substituted).

[0109] The hydroxamic acid derivatives described herein can, as notedabove, be prepared in the form of their pharmaceutically acceptablesalts. Pharmaceutically acceptable salts are salts that retain thedesired biological activity of the parent compound and do not impartundesired toxicological effects. Examples of such salts are (a) acidaddition salts formed with inorganic acids, for example hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; and salts formed with organic acids such as, for example,acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid,fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid,benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamicacid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonicacid, naphthalenedisulfonic acid, polygalacturonic acid, and the like;(b) salts formed from elemental anions such as chlorine, bromine, andiodine, and (c) salts derived from bases, such as ammonium salts, alkalimetal salts such as those of sodium and potassium, alkaline earth metalsalts such as those of calcium and magnesium, and ferric salts as wellas salts with organic bases such as isopropylamine, trimethylamine,2-ethylamino ethanol, histidine, procaine, dicyclohexylamine andN-methyl-D-glucamine.

[0110] The active compounds disclosed can, as noted above, be preparedin the form of their hydrates, such as hemihydrate, monohydrate,dihydrate, trihydrate, tetrahydrate and the like and as solvates.

[0111] Stereochemistry

[0112] Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and l or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture.

[0113] Many of the compounds described herein can have one or morechiral centers and therefore can exist in different enantiomeric forms.If desired, a chiral carbon can be designated with an asterisk (*). Whenbonds to the chiral carbon are depicted as straight lines in theformulas of the invention, it is understood that both the (R) and (S)configurations of the chiral carbon, and hence both enantiomers andmixtures thereof, are embraced within the formula. As is used in theart, when it is desired to specify the absolute configuration about achiral carbon, one of the bonds to the chiral carbon can be depicted asa wedge (bonds to atoms above the plane) and the other can be depictedas a series or wedge of short parallel lines is (bonds to atoms belowthe plane). The Cahn-Inglod-Prelog system can be used to assign the (R)or (S) configuration to a chiral carbon.

[0114] When compounds of the present invention contain one chiralcenter, the compounds exist in two enantiomeric forms and the presentinvention includes both enantiomers and mixtures of enantiomers, such asthe specific 50:50 mixture referred to as a racemic mixtures. Theenantiomers can be resolved by methods known to those skilled in theart, for example by formation of diastereoisomeric salts which may beseparated, for example, by crystallization (See, CRC Handbook of OpticalResolutions via Diastereomeric Salt Formation by David Kozma (CRC Press,2001)); formation of diastereoisomeric derivatives or complexes whichmay be separated, for example, by crystallization, gas-liquid or liquidchromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. It will be appreciated that where thedesired enantiomer is converted into another chemical entity by one ofthe separation procedures described above, a further step is required toliberate the desired enantiomeric form. Alternatively, specificenantiomers may be synthesized by asymmetric synthesis using opticallyactive reagents, substrates, catalysts or solvents, or by converting oneenantiomer into the other by asymmetric transformation.

[0115] Designation of a specific absolute configuration at a chiralcarbon of the compounds of the invention is understood to mean that thedesignated enantiomeric form of the compounds is in enantiomeric excess(ee) or in other words is substantially free from the other enantiomer.For example, the “R” forms of the compounds are substantially free fromthe “S” forms of the compounds and are, thus, in enantiomeric excess ofthe “S” forms. Conversely, “S” forms of the compounds are substantiallyfree of “R” forms of the compounds and are, thus, in enantiomeric excessof the “R” forms. Enantiomeric excess, as used herein, is the presenceof a particular enantiomer at greater than 50%. For example, theenantiomeric excess can be about 60% or more, such as about 70% or more,for example about 80% or more, such as about 90% or more. In aparticular embodiment when a specific absolute configuration isdesignated, the enantiomeric excess of depicted compounds is at leastabout 90%. In a more particular embodiment, the enantiomeric excess ofthe compounds is at least about 95%, such as at least about 97.5%, forexample, at least 99% enantiomeric excess.

[0116] When a compound of the present invention has two or more chiralcarbons it can have more than two optical isomers and can exist indiastereoisomeric forms. For example, when there are two chiral carbons,the compound can have up to 4 optical isomers and 2 pairs of enantiomers((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g.,(S,S)/(R,R)) are mirror image stereoisomers of one another. Thestereoisomers which are not mirror-images (e.g., (S,S) and (R,S)) arediastereomers. The diastereoisomeric pairs may be separated by methodsknown to those skilled in the art, for example chromatography orcrystallization and the individual enantiomers within each pair may beseparated as described above. The present invention includes eachdiastereoisomer of such compounds and mixtures thereof.

[0117] As used herein, “a,” an” and “the” include singular and pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “an active agent” or “a pharmacologically activeagent” includes a single active agent as well a two or more differentactive agents in combination, reference to “a carrier” includes includesmixtures of two or more carriers as well as a single carrier, and thelike.

[0118] Method of Treatment

[0119] The invention also relates to methods of using the hydroxamicacid derivatives described herein.

[0120] In one embodiment, the invention relates to a method of treatingcancer in a subject in need of treatment comprising administering tosaid subject a therapeutically effective amount of a hydroxamic acidcompound described herein.

[0121] As used herein, cancer refers to tumors, neoplasms, carcinomas,sarcomas, leukemias, lymphomas and the like. For example, cancersinclude, but are not limited to, leukemias and lymphomas such ascutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-celllymphoma, lymphomas associated with human T-cell lymphotropic virus(HTLV), for example, adult T-cell leukemia/lymphoma (ATLL), acutelymphocytic leukemia, acute nonlymphocytic leukemias, chroniclymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease,non-Hodgkin's lymphomas, and multiple myeloma, childhood solid tumorssuch as brain tumors, neuroblastoma, retinoblastoma, Wilms Tumor, bonetumors, and soft-tissue sarcomas, common solid tumors of adults such ashead and neck cancers (e.g., oral, laryngeal and sophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian,testicular, rectal and colon), lung cancer, breast cancer, pancreaticcancer, melanoma and other skin cancers, stomach cancer, brain tumors,liver cancer and thyroid cancer.

[0122] In another embodiment, the method of use is a method ofselectively inducing terminal differentiation of neoplastic cells andthereby inhibiting proliferation of such cells. The method comprisescontacting the cells under suitable conditions with an effective amountof a hydroxamic acid compound described herein.

[0123] In another embodiment, the hydroxamic acid derivatives are usedin a method of selectively inducing cell growth arrest of neoplasticcells and thereby inhibiting proliferation of such cells. The methodcomprises contacting the cells under suitable conditions with aneffective amount of a hydroxamic acid compound described herein.

[0124] In yet another embodiment, the hydroxamic acid derivatives areused in a method of inducing terminal differentiation of tumor cells ina tumor comprising contacting the cells with an effective amount of ahydroxamic acid compounds described herein.

[0125] In still another embodiment, the hydroxamic acid derivatives areused in a method of inhibiting the activity of histone deacetylasecomprising contacting the histone deacetylase with an effective amountof one or more of the hydroxamic acid compouonds described herein.

[0126] In another embodiment, the hydroxamic acid derivatives are usedin a method of treating a thioredoxin (TRX)-mediated disease or disorderin a subject in need thereof, comprising administering to the subject atherapeutically effective amount of one or more of the hydroxamic acidcompounds described herein.

[0127] Examples of TRX-mediated diseases include, but are not limitedto, acute and chronic inflammatory diseases, autoimmune diseases,allergic diseases, diseases associated with oxidative stress, anddiseases characterized by cellular hyperproliferation.

[0128] Non-limiting examples are inflammatory conditions of a jointincluding rheumatoid arthritis (RA) and psoriatic arthritis;inflammatory bowel diseases such as Crohn's disease and ulcerativecolitis; spondyloarthropathies; scleroderma; psoriasis (including T-cellmediated psoriasis) and inflammatory dermatoses such an dermatitis,eczema, atopic dermatitis, allergic contact dermatitis, urticaria;vasculitis (e.g., necrotizing, cutaneous, and hypersensitivityvasculitis); eosinphilic myositis, eosinophilic fasciitis; cancers withleukocyte infiltration of the skin or organs, ischemic injury, includingcerebral ischemia (e.g., brain injury as a result of trauma, epilepsy,hemorrhage or stroke, each of which may lead to neurodegeneration); HIV,heart failure, chronic, acute or malignant liver disease, autoimmunethyroiditis; systemic lupus erythematosus, Sjorgren's syndrome, lungdiseases (e.g., ARDS); acute pancreatitis; amyotrophic lateral sclerosis(ALS); Alzheimer's disease; cachexia/anorexia; asthma; atherosclerosis;chronic fatigue syndrome, fever; diabetes (e.g., insulin diabetes orjuvenile onset diabetes); glomerulonephritis; graft versus hostrejection (e.g., in transplantation),; hemohorragic shock; hyperalgesia:inflammatory bowel disease; multiple sclerosis; myopathies (e.g., muscleprotein metabolism, esp. in sepsis); osteoporosis; Parkinson's disease;pain; pre-term labor; psoriasis; reperfusion injury; cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock); side effects fromradiation therapy, temporal mandibular joint disease, tumor metastasis;or an inflammatory condition resulting from strain, sprain, cartilagedamage, trauma such as burn, orthopedic surgery, infection or otherdisease processes. Allergic diseases and conditions, include but are notlimited to respiratory allergic diseases such as asthma, allergicrhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilicpneumonia), delayed-type hypersentitivity, interstitial lung diseases(ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated withrheumatoid arthritis, systemic lupus erythematosus, ankylosingspondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis ordermatomyositis); systemic anaphylaxis or hypersensitivity responses,drug allergies (e.g., to penicillin, cephalosporins), insect stingallergies, and the like.

[0129] In another embodiment, the hydroxamic acid derivatives are usedin a method of treating a disease of the central nervous system in asubject in need thereof comprising administering to the subject atherapeutically effective amount of any one or more of the hydroxamicacid compounds described herein.

[0130] In a particular embodiment, the CNS disease is aneurodegenerative disease. In a further embodiment, the neurogenerativedisease is an inherited neurodegenerative disease, such as thoseinherited neurodegenerative diseases which are polyglutamine expansiondiseases.

[0131] Generally, neurodegenerative diseases can be grouped as follows:

[0132] I. Disorders characterized by progressive dementia in the absenceof other prominent neurologic signs.

[0133] A. Alzheimer's disease

[0134] B. Senile dementia of the Alzheimer type

[0135] C. Pick's disease (lobar atrophy)

[0136] II. Syndromes combining progressive dementia with other prominentneurologic abnormalities

[0137] A. Mainly in adults

[0138] 1. Huntington's disease

[0139] 2. Multiple system atrophy combining dementia with ataxia and/ormanifestations of Parkinson's disease

[0140] 3. Progressive supranuclear aplsy (Steel-Richardson-Olszewski)

[0141] 4. Diffuse Lewy body disease

[0142] 5. Corticodentatonigral degeneration

[0143] B. Mainly in children or young adults

[0144] 1. Hallervorden-Spatz disease

[0145] 2. Progressive familial myoclonic epilepsy

[0146] II. Syndromes of gradually developing abnormalities of postureand movement

[0147] A. Paralysis agitans (Parkinson's disease)

[0148] B. Striatonigral degeneration

[0149] C. Progressive supranuclear palsy

[0150] D. Torsion dystonia (torsion spasm; dystonia musculorumdeformans)

[0151] E. Spasmodic torticollis and other dyskinesis

[0152] F. Familial tremor

[0153] G. Gilles de la Tourette syndrome

[0154] IV. Syndromes of progressive ataxia

[0155] A. Cerebellar degenerations

[0156] 1. Cerebellar cortical degeneration

[0157] 2. Olivopontocerebellar atrophy (OPCA)

[0158] B. Spinocerebellar degeneration (Friedreich's atazia and relateddisorders)

[0159] V. Syndrome of central autonomic nervous system failure(Shy-Drager syndrome)

[0160] VI. Syndromes of muscular weakness and wasting without sensorychanges (motor neuron disease)

[0161] A. Amyotrophic lateral sclerosis

[0162] B. Spinal muscular atrophy

[0163] 1. Infantile spinal muscular atrophy (Werdnig-Hoffman)

[0164] 2. Juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander)

[0165] 3. Other forms of familial spinal muscular atrophy

[0166] C. Primary lateral sclerosis

[0167] D. Hereditary spastic paraplegia

[0168] VII. Syndromes combining muscular weakness and wasting withsensory changes (progressive neural muscular atrophy; chronic familialpolyneuropathies)

[0169] A. Peroneal muscular atrophy (Charcot-Marie-Tooth)

[0170] B. Hypertrophic interstitial polyneuropathy (Dejerine-Sottas)

[0171] C. Miscellaneous forms of chronic progressive neuropathy

[0172] VIII Syndromes of progressive visual loss

[0173] A. Pigmentary degeneration of the retina (retinitis pigmentosa)

[0174] B. Hereditary optic atrophy (Leber's disease)

[0175] As used herein, therapeutically effective or effective amountrefers to an amount which elicits the desired therpeutic or biologicaleffect. The therapeutic effect is dependent upon the disease or disorderbeing treated or the biological effect desired. As such, the therapeuticeffect can be a decrease in the severity of symptoms associated with thedisease or disorder and/or inhibition (partial or complete) ofprogression of the disease. The amount needed to elicit the therapeuticresponse can be determined based on the age, health, size and sex of thesubject. Optimal amounts can also be determined based on monitoring ofthe subject's response to treatment.

[0176] For example, when the method is a method of treating cancer, atherapeutically effective amount can be an amount which is inhibits(partially or totally) the formation of a tumor or a hematologicalmalignancy, reverses the development of a tumor or other malignancy,prevents or reduces its further progression, prevents its development(chemopreventive) or treats cancer metastases.

[0177] Further, a therapeutically effective amount, can be an amountwhich selectively induces terminal differentiation of neoplastic cells,an amount which selectively induces cell growth arrest of neoplasticcells or an amount that induces terminal differentiation of tumor cells.

[0178] When the method is a method for treating and/or preventingthioredoxin (TRX)-mediated diseases and conditions, a therapeuticallyeffective amount is an amount which regulates, for example, increases,decreases or maintains a physiologically suitable level of TRX in thesubject in need of treatment to elicit the desired therapeutic effect.The therapeutic effect is dependent upon the specific TRX-mediateddisease or condition being treated. As such, the therapeutic effect canbe a decrease in the severity of symptoms associated with the disease ordisorder and/or inhibition (partial or complete) of progression of thedisease or disease.

[0179] In addition, a therapeutically effective amount can be an amountwhich inhibits histone deacetylase.

[0180] Subject, as used herein, refers to animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice orother bovine, ovine, equine, canine, feline, rodent or murine species.

[0181] Pharmaceutical Compositions

[0182] The compounds of the invention, and derivatives, fragments,analogs, homologs pharmaceutically acceptable salts, hydrates orsolvates thereof, can be incorporated into pharmaceutical compositionssuitable for various modes of administration, together with apharmaceutically acceptable carrier or excipient. Such compositionstypically comprise a therapeutically effective amount of any of thecompounds above, and a pharmaceutically acceptable carrier.

[0183] The hydroxamic acid derivatives can be administered in such oralforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixers,tinctures, suspensions, syrups, and emulsions. Likewise, the hydroxamicacid derivatives can be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using formswell known to those of ordinary skill in the pharmaceutical arts.

[0184] Routes of administration also include any other conventional andphysiologically acceptable route, such as, for example, inhalation (viaa fine powder formulation or a fine mist), transdermal, nasal, vaginal,rectal, or sublingual routes of administration and can be formulated indosage forms appropriate for each route of administration.

[0185] The hydroxamic acid derivatives of the present invention can alsobe administered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine or phosphatidylcholines.

[0186] The hydroxamic acid derivatives can also be delivered by the useof monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The hydroxamic acid derivatives can also beprepared with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinlypyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the Hydroxamic acidderivatives can be prepared with biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross linked oramphipathic block copolymers of hydrogels.

[0187] The hydroxamic acid derivatives can be administered as activeingredients in admixture with suitable pharmaceutical diluents,excipients or carriers (collectively referred to herein as “carrier”materials) suitably selected with respect to the intended form ofadministration, and consistent with conventional pharmaceuticalpractices.

[0188] For instance, for oral administration in the form of a tablet orcapsule, the hydroxamic acid derivative can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier. Solidcarriers/diluents include, but are not limited to, a gum, a starch(e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.,microcrystalline cellulose), an acrylate (e.g., polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

[0189] For liquid formulations, pharmaceutically acceptable carriers maybe aqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, emulsions orsuspensions, including saline and buffered media. Examples of oils arethose of petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, andfish-liver oil. Solutions or suspensions can also include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid(EDTA); buffers such as acetates, citrates or phosphates, and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

[0190] In addition, the compositions may further comprise binders (e.g.,acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone),disintegrating agents (e.g., cornstarch, potato starch, alginic acid,silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodiumstarch glycolate, Primogel), additives such as albumin or gelatin toprevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80,Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g.,sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g.,glycerol, polyethylene glycerol), a glidant (e.g., colloidal silicondioxide), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite,butylated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose,hyroxypropylmethyl cellulose), viscosity increasing agents (e.g.,carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum),sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents(e.g., peppermint, methyl salicylate, or orange flavoring),preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants(e.g., stearic acid, magnesium stearate, polyethylene glycol, sodiumlauryl sulfate), flow-aids (e.g., colloidal silicon dioxide),plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers(e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate),polymer coatings (e.g., poloxamers or poloxamines), coating and filmforming agents (e.g., ethyl cellulose, acrylates, polymethacrylates)and/or adjuvants.

[0191] In addition, buffers (e.g.,) of various pH and ionic strength canbe used in the formulations. Tris-HCI., Phosphate Glucuronic acid,L-lactic acid, acetic acid, citric acid or any pharmaceuticallyacceptable acid/conjugate base with reasonable buffering capacity in thepH range acceptable for intravenous administration of the hydroxamicacid derivative can be used as buffers. Sodium chloride solution whereinthe pH has been adjusted to the desired range with either acid or base,for example, hydrochloric acid or sodium hydroxide, can also beemployed. Typically, a pH range for the intravenous formulation can bein the range of from about 5 to about 12. A preferred pH range forintravenous formulation wherein can be about 9 to about 12.Consideration should be given to the solubility and chemicalcompatibility of the compound in choosing an appropriate excipient.

[0192] Subcutaneous formulations, preferably prepared according toprocedures well known in the art at a pH in the range between about 5and about 12, also include suitable buffers and isotonicity agents. Theycan be formulated to deliver a daily dose of the active compound in oneor more daily subcutaneous administrations, e.g., one, two or threetimes each day. The choice of appropriate buffer and pH of aformulation, depending on solubility of the hydroxamic acid derivativeto be administered, is readily made by a person having ordinary skill inthe art. Sodium chloride solution wherein the pH has been adjusted tothe desired range with either acid or base, for example, hydrochloricacid or sodium hydroxide, can also be employed in the subcutaneousformulation. Typically, a pH range for the subcutaneous formulation canbe in the range of from about 5 to about 12. A preferred pH range forsubcutaneous formulation can be about 9 to about 12. Considerationshould be given to the solubility and chemical compatibility of thehydroxamic acid derivative in choosing an appropriate excipient.

[0193] The hydroxamic acid derivatives can also be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,or course, be continuous rather than intermittent throughout the dosageregime.

[0194] In the treatment of rheumatoid arthritis the hydroxamic acidderivative can be administered directly into the synovial fluid and/orsynovial tissue of the rheumatic joint such that a local effect of theinhibitor is realized.

[0195] In one embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0196] It is especially advantageous to formulate oral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the subject to be treated; each unitcontaining a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms ofthe invention are dictated by and directly dependent on the uniquecharacteristics of the active compound and the particular therapeuticeffect to be achieved, and the limitations inherent in the art ofcompounding such an active compound for the treatment of individuals.

[0197] The pharmaceutical compositions can be included in a container,pack, or dispenser together with instructions for administration.

[0198] The preparation of pharmaceutical compositions that contain anactive component is well understood in the art, for example, by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients that are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the active agents are mixed with additives customary forthis purpose, such as vehicles, stabilizers, or inert diluents, andconverted by customary methods into suitable forms for administration,such as tablets, coated tablets, hard or soft gelatin capsules, aqueous,alcoholic or oily solutions and the like as detailed above.

[0199] Dosing

[0200] The dosage regimen utilizing the compounds of the presentinvention can be selected in accordance with a variety of factorsincluding type, species, age, weight, sex and the disease being treated;the severity of the condition to be treated; the route ofadministration; the renal and hepatic function of the patient; and theparticular compound or salt thereof employed. An ordinarily skilledphysician or veterinarian can readily determine and prescribe theeffective amount of the drug required to treat, for example, to prevent,inhibit (fully or partially) or arrest the progress of the disease.

[0201] Oral dosages of the hydroxamic acid derivatives, when used totreat the desired disease, can range between about 2 mg to about 2000 mgper day, such as from about 20 mg to about 2000 mg per day, such as fromabout 200 mg to about 2000 mg per day. For example, oral dosages can beabout 2, about 20, about 200, about 400, about 800, about 1200, about1600 or about 2000 mg per day. It is understood that the total amountper day can be administered in a single dose or can be administered inmultiple dosings such as twice, three or four times per day.

[0202] For example, a patient can receive between about 2 mg/day toabout 2000 mg/day, for example, from about 20-2000 mg/day, such as fromabout 200 to about 2000 mg/day, for example from about 400 mg/day toabout 1200 mg/day. A suitably prepared medicament for once a dayadministration can thus contain between about 2 mg and about 2000 mg,such as from about 20 mg to about 2000 mg, such as from about 200 mg toabout 1200 mg, such as from about 400 mg/day to about 1200 mg/day. TheHydroxamic acid derivatives can be administered in a single dose or individed doses of two, three, or four times daily. For administrationtwice a day, a suitably prepared medicament would therefore contain halfof the needed daily dose.

[0203] Intravenously or subcutaneously, the patient would receive thehydroxamic acid derivative in quantities sufficient to deliver betweenabout 3-1500 mg/m² per day, for example, about 3, 30, 60, 90, 180, 300,600, 900, 1200 or 1500 mg/m² per day. Such quantities may beadministered in a number of suitable ways, e.g. large volumes of lowconcentrations of Hydroxamic acid derivative during one extended periodof time or several times a day. The quantities can be administered forone or more consecutive days, intermittent days or a combination thereofper week (7 day period). Alternatively, low volumes of highconcentrations of the hydroxamic acid derivative during a short periodof time, e.g. once a day for one or more days either consecutively,intermittently or a combination thereof per week (7 day period). Forexample, a dose of 300 mg/m² per day can be administered for consecutivedays for a total of 1500 mg/m² per treatment. In another dosing regimen,the number of consecutive days can also be, with treatment lasting for 2or 3 consecutive weeks for a total of 3000 mg/m2 and 4500 mg/m² totaltreatment.

[0204] Typically, an intravenous formulation may be prepared whichcontains a concentration of a hydroxamic acid derivative of betweenabout 1.0 mg/mL to about 10 mg/mL, e.g. 2.0 mg/mL, 3.0 mg/mL, 4.0 mg/mL,5.0 mg/mL, 6.0 mg/mL, 7.0 mg/mL, 8.0 mg/mL, 9.0 mg/mL and 10 mg/mL andadministered in amounts to achieve the doses described above. In oneexample, a sufficient volume of intravenous formulation can beadministered to a patient in a day such that the total dose for the dayis between about300 and about 1500 mg/m2.

[0205] Combination Therapy

[0206] The hydroxamic acid compounds of the present invention can beadministered alone or in combination withother therapies suitable forthe disease or disorder being treated. Where separate dosageformulations are used, the hydroxamic acid compound and the othertherapeutic agent can be administered at essentially the same time(concurrently) or at separately staggered times (sequentially). Thepharmaceutical combination is understood to include all these regimens.Administration in these various ways are suitable for the presentinvention as long as the beneficial therapeutic effect of the hydroxamicacid compound and the other therapeutic agent are realized by thepatient at substantially the same time. Such beneficial effect ispreferably achieved when the target blood level concentrations of eachactive drug are maintained at substantially the same time.

[0207] In one embodiment, the present invention provides the hydroxamicacid compounds described herein in combination with an antitumor agent,a hormone, a steroid, or a retinoid.

[0208] A suitable antitumor agent can be one of numerous chemotherapyagents such as an alkylating agent, an antimetabolite, a hormonal agent,an antibiotic, colchicine, a vinca alkaloid, L-asparaginase,procarbazine, hydroxyurea, mitotane, nitrosoureas or an imidazolecarboxamide. Suitable agents are those agents which promotedepolarization of tubulin. Preferably the antitumor agent is colchicineor a vinca alkaloid; especially preferred are vinblastine andvincristine.

[0209] Experimental

EXAMPLE 1 Synthesis

[0210] The compounds of the present invention were prepared by thegeneral method outlined in the synthetic schemes below, as exemplifiedbelow for Compounds 1 and 6. TABLE 1

COMPOUND DESCRIPTION Compound No. Ar₁ Ar₂ MW 1 6-quinolinyl O(CH2)Ph464.5 6 6-quinolinyl Phenyl 434.5

[0211] Briefly, the generation of the amino-suberates started withcommercially available doubly-protected amino-suberate (Scheme 1). Thedicyclohexylamine salt was removed with aqueous hydrogen chloride toyield the free acid. Typical amide coupling yielded the Cbz-protectedamine, which was deprotected and acylated to the diester. Thehydrogenolysis was bypassed for 6a, since the final product containedthe Cbz moiety. The acids were protected with TFA in CH₂Cl₂, and thefinal hydroxamic acid formation was achieved via mixed anhydrideformation and quenching with hydroxylamine.

(7S)-7-BENZYLOXYCARBONYLAMINO-OCTANEDIOIC ACID 8-TERT-BUTYL ESTER (1)

[0212] To a slurry of commercially available dicyclohexylamine salt ofN-Cbz-(L)-Asu(OtBu) (9.0 g, 16.1 mmol) in EtOAc (500 mL) was added 1NHCl (160 mL). The resultant slurry was shook in a separatory funnel andfiltered. The aqueous layer was extracted further with EtOAc, and thecombined organic layers were washed with 1N HCl (60 mL), and H2O (60mL). The organic layer was dried, filtered, and concentrated underreduced pressure to yield a clear oil 6.2 g, which was used withoutfurther purification.

(7S)-7-BENZYLOXYCARBONYLAMINO-7-(QUINOLIN-6-YLCARBAMOYL)-HEPTANOIC ACIDTERT-BUTYL ESTER (2)

[0213] (7S)-7-Benzyloxycarbonylamino-octanedioic acid 8-tert-butyl ester(10.0 g, 26.3 mmol), 6-aminoquinoline (4.02 g, 27.9 mmol) and EDCI (6.07g, 29.0 mmol) were dissolved in 150 mL anhydrous CH₃CN. The solution wasstirred at RT for 2 h. The solvent was removed under reduced pressure,and the residue was dissolved in 500 mL EtOAc and washed with 1 M HCl(200×3) and water (100×2). The organic layer was dried over anhydrousNa₂SO₄ Removal of solvent gave 16 g crude product. The pure compound 9.0g was obtained with column separation (ethyl acetate as eluent) in 68%as a thick oil. ¹H NMR (CDCl₃) δ 8.80 (1H, d), 8.70 (1H, s), 8.30 (1H,d), 8.00 (2H, t), 7.56-7.20 (7H), 5.40 (1H, d), 5.08 (2H, s), 4.38 (1H,m), 2.20 (2H, t), 2.0-1.6 (17H, m). MS (ESI): (MH⁺) 506.3.

(7S)-7-AMINO-7-(QUINOLIN-6-YLCARBAMOYL)-HEPTANOIC ACID TERT-BUTYL ESTER(3b)

[0214] To a stirring solution of(7S)-7-benzyloxycarbonylamino-7-(quinolin-6-ylcarbamoyl)-heptanoic acidtert-butyl ester (11.0 g, 21.8 mmol) in EtOAc and MeOH was added 10%Pd/C. The reaction was charged with H₂, degassed and refilled withhydrogen three times. The slurry was stirred at RT for 2 h at balloonpressure, then filtered through a plug of Celite, and solvent wasremoved under reduced pressure. The hydrogenolysis of the ester yielded8.0 g (99%) of a thick oil solid after 19 h. ¹H NMR (CDCl₃) δ 8.9-7.3(7H, m), 3.96 (1H, m), 2.31 (2H, t), 2.0-1.2 (17H, m). MS (ESI): (MH⁺)372.2.

(7S)-7-BENZOYLAMINO-7-(QUINOLIN-6-YLCARBAMOYL)-HEPTANOIC ACID TERT-BUTYLESTER (4b)

[0215] To a stirring solution of(7S)-7-amino-7-(quinolin-6-ylcarbamoyl)-heptanoic acid tert-butyl ester(8.0 g, 21.6 mmol) in dry MeCN (100 mL) and to this solution was addedbenzoyl chloride (2.78 mL, 23.8 mmol) and triethylamine (6.1 mL, 43.2mmol). The solution was stirred at 0° C. for 1 h, then at RT for 2 h.The solvent was removed, and residue was dissolved in 400 mL EtOAc, andstirred with 100 mL 0.5 M NaHCO₃ for 1 h. The aqueous layer was removed,and the organic layer was washed with 100 mL 0.5 M NaHCO₃, then with 50mL water. The solution was dried over anhydrous Na₂SO₄. The product (8.1g) was obtained after column purification (EtOAc as eluent) in 78.8%yield as a thick oil. ¹H NMR (CDCl₃) δ 9.40 (1H, s), 8.80 (1H, d), 8.22(1H, d), 8.0-7.0 (10H, m), 5.0 (1H, m), 2.2-1.2 (19H, m). MS (ESI):(MH⁺) 476.1.

(7S)-7-BENZOYLAMINO-7-(QUINOLIN-6-YLCARBAMOYL)-HEPTANOIC ACID (5b)

[0216] TFA deprotection of the t-butyl ester (8.45 g, 17.8 mmol) inCH₂Cl₂ (40 mL) and TFA (10 mL) was stirred for 24 h. The solvent wasremoved under reduced pressure and the residue was dissolved in 300 mLEtOAc. The solution was adjusted to pH 4 with aq. NaHCO₃, and theorganic phase was collected. The aqueous phase was extracted with ethylacetate (2×100 mL). The combined ethyl acetate fractions were dried overanhydrous Na₂SO₄. The solvent was removed, and the resulting residue wasstirred with methylene chloride to give an off white solid 6.9 g withyield of 93.5% ¹H NMR (DMSO-d6) δ 10.6 (1H, s), 8.82 (1H, d), 8.76 (1H,d), 8.4-7.4 (10H, m), 4.60 (1H, m), 2.2 (2H, t), 1.8-1.2 (8H, m). MS(ESI): (MH⁺) 420.1.

(7S)-7-BENZYLOXYCARBONYLAMINO-7-(QUINOLIN-6-YLCARBAMOYL)-HEPTANOIC ACID(5a)

[0217] The same procedure as for the preparation of Compound 5a((7S)-7-Benzoylamino-7-(quinolin-6-ylcarbamoyl)-heptanoic acid) wasemployed. TFA deprotection of the t-butyl ester (9.0 g, 17.8 mmol)yielded 7.4 g (92.5%) of an off white solid after 24 h. ¹H NMR (DMSO) δ10.6 (1H, s), 8.82 (1H, d), 8.76 (1H, d), 8.4-7.4 (10H, m), 5.0 (2H, s),4.20 (1H, m), 2.4 (2H, t), 1.8-1.2 (8H, m). MS (ESI): (MH⁺) 450.2.

(2S)-2-BENZOYLAMINO-OCTANEDIOIC ACID 8-HYDROXYAMIDE 1-QUINOLIN-6-YLAMIDE(6b)

[0218] The acid (2.33 g, 5.57 mmol) was mixed withiso-butylchloroformate (2.19 mL, 16.7 mmol), NMM (2.1 mL, 18.9 mmol),and 4.0 equiv. of hydroxylamine (prepared as previously stated withexcess hydroxylamine.HCl and NaOH) in MeCN and yielded a solid aftersolvent removal. The solid was stirred with 30 mL EtOAc and aq. sodiumbicarbonate (30 mL) for 20 min. The solid was triturated with EtOAc (60mL), xylene/MeOH (100 mL, 2:1), chloroform (60 mL), MeCN (100 mL),xylene/MeOH (100 mL, 2:1) and acetone (60 mL) respectively yielding awhite solid (58.7%) with purity over 97%. ¹H NMR (CDCl₃) δ 10.4 (1H, d),8.8-7.4 (13H, m), 4.60 (1H, m), 2.45 (1H, s), 1.9-1.3 (9H, m). MS (ESI):(MH⁺) 435.1.

(S)-[6-HYDROXYCARBAMOYL-1-(QUINOLIN-6-YLCARBAMOYL)-HEXYL]-CARBAMIC ACIDBENZYL ESTER (6a)

[0219] The acid (2.5 g, 5.57 mmol) was mixed with iso-butylchloroformate(2.19 mL, 16.7 mmol), NMM (2.1 mL, 18.9 mmol), and 4.0 equiv. ofhydroxylamine hydroxylamine (prepared as previously stated with excesshydroxylamine.HCl and NaOH) in MeCN and yielded a solid after solventremoval. The solid was stirred with 30 mL EtOAc and aq. sodiumbicarbonate (30 mL) for 20 min. The solid was triturated with EtOAc (60mL), xylene/MeOH (100 mL, 2:1), chloroform (60 mL), MeCN (100 mL),xylene/MeOH (100 mL, 2:1) and acetone (60 mL) respectively yielding awhite solid (67.6%) with purity over 97%. ¹H NMR (DMSO) δ 10.4 (1H, d),8.8-7.3 (13H, m), 5.04 (2H, s), 4.20 (1H, m), 2.45 (2H, t), 1.9-1.2 (8H,m). MS (ESI): (MH⁺) 465.4.

[0220] Alternative Synthesis

[0221] An alterative synthesis was developed to reduce the number ofsynthetic steps, and reduce the overall cost of the reaction pathway.The synthesis started with the Boc-protected methyl ester amino-suberateI (Scheme 2). Amide formation was carried out using standard peptidecoupling methodology. TFA deprotection yielded the amine-TFA salt, whichwas acylated using the requisite acid chloride, affording III. Formationof IV was accomplished in one step with methyl-ester III andhydroxylamine. Compound 6 was prepared according to the aternatesynthesis and isolated as the racemic mixture due to the use of racemicstarting material (1).

EXAMPLE 2 HDAC Inhibition by Novel Compounds

[0222] HDAC1-Flag Assay:

[0223] Novel compounds were tested for their ability to inhibit histonedeacetylase, subtype 1 (HDAC1) using an in vitro deacetylation assay.The enzyme source for this assay was an epitope-tagged human HDAC1complex immuno-purified from stably expressing mammalian cells. Thesubstrate consisted of a commercial product containing an acetylatedlysine side chain (Biomol, Plymouth Meeting, Pa.). Upon deacetylation ofthe substrate by incubation with the purified HDAC1 complex, afluorophore is produced that is directly proportional to the level ofdeacetylation. Using a substrate concentration at the Km for the enzymepreparation, the deacetylation assay was performed in the presence ofincreasing concentrations of novel compounds to semi-quantitativelydetermine the concentration of compound required for 50% inhibition(IC₅₀) of the deacetylation reaction.

[0224] Results:

[0225] Table 2 below shows the chemical structures and HDAC enzymaticassay results for a selection of novel compounds designed andsynthesized in accordance with the present invention. Additionalcompounds are shown in Table 4, below. TABLE 2 HDAC Mol. Inhibition No.Structure Formula MW IC50,nM 6a

C₂₅H₂₈N₄O₅ 464.5 5.9 2

C₂₃H₂₉N₃O₅ 427.5 37.4 3

C₂₅H₂₈N₄O₄ 448.5 52.7 4

C₂₅H₂₇N₃O₄ 397.5 73.0 5

C₂₁H₂₆N₄O₄ 398.5 149.8 6b

C₂₄H₂₆N₄O₄ 434.5 1.8 7

C₂₇H₂₇N₅O₄ 485.5 54.5 8

C₂₃H₂₅N₅O₄ 435.5 1.6 9

C₂₃H₂₅N₅O₄ 435.5 4.1 10

C₂₇H₂₇N₅O₄ 485.5 41.8 11

C₂₄H₂₆N₄O₄ 434.5 12.7

EXAMPLE 3 Proliferation Assay

[0226] Proliferation

[0227] The novel compounds of the present invention were tested fortheir ability to inhibit growth of the human bladder carcinoma cellline, T24. Cells were treated with compounds for 72 hours, lysed byfreeze/thaw to expose the DNA, and then the DNA was quantitated usingthe intercalating dye, bisbenzamide (Sigma). Fluorescent intensity (ex350λ em 460λ) was directly proportional to the number of cells per well.Fluorescence values from vehicle-treated cells were determined and usedas 100%. The concentration of compound required to inhibit cell growthby 50% was determined and is reported in Table 3.

[0228] Results:

[0229] The results of the T24 cell-based proliferation assay from aselect group of novel compounds are summarized in Table 3 below:Compound Cell Growth No. Inhbition, IC₅₀  6a 0.2  2 1.4  3 1.7  4 3.2  59.2  6b 0.2  7 0.6  8 1.8  9 0.4 10 1.4 11 0.3

[0230] TABLE 4 HDAC Molecular inhibition No. Structure Formula MWIC50(nM) 12

C₂₃H₂₉N₃O₄ 411.4998 156 + 22.6 (n = 2) 13

C₂₅H₃₃N₃O₄ 439.5534 185.5 + 21.9 (n = 2)

[0231] While this invention has been particularly shown an describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A compound represented by the followingstructural formula:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein: R₁ is a substituted or unsubstituted aryl group, arylalkylgroup, arylamino group, arylalkylamino group, aryloxy group orarylalkoxy group; and n is an integer from 3 to
 10. 2. The compound ofclaim 1, wherein n is
 5. 3. The compound of claim 1, wherein R₁ is asubstituted or unsubstituted heteroaryl group, phenyl group or naphthylgroup.
 4. The compound of claim 1, wherein R₁ is a substituted orunsubstituted pyridyl group, quinolinyl group or isoquinolinyl group. 5.The compound of claim 1, wherein R₁ is a substituted or unsubstitutedphenyl group.
 6. The compound of claim 5, wherein R₁ is an unsubstitutedphenyl group.
 7. The compound of claim 6, wherein n is
 5. 8. Thecompound of claim 1, wherein R₁ is an unsubstituted pyridyl group. 9.The compound of claim 8, wherein R₁ is β-pyridyl.
 10. The compound ofclaim 9, wherein n is
 5. 11. The compound of claim 1, wherein R₁ is anunsubstituted quinolinyl group.
 12. The compound of claim 11, wherein R₁is a 2-quinolinyl group.
 13. The compound of claim 12, wherein n is 5.14. The compound of claim 1, wherein R₁ is a substituted orunsubstituted arylalkyloxy group.
 15. The compound of claim 14, whereinR₁ is substituted or unsubstituted benzyloxy group.
 16. The compound ofclaim 15, wherein R₁ is an unsubstituted benzyloxy group.
 17. Thecompound of claim 16, wherein n is
 5. 18. A compound represented by thefollowing structural formula:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein: Q₁ is a substituted or unsubstituted quinolinyl orisoquinolinyl group; n is an integer from 3 to
 10. 19. The compound ofclaim 18, wherein Q₁ is an 8-quinolinyl group.
 20. The compound of claim18 wherein the pyridyl group is β-pyridyl.
 21. The compound of claim 20wherein Q₁ is an 8-quinolinyl group.
 22. The compound of claim 21,wherein n is
 5. 23. A compound represented by the following structuralformula:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein: Q₁ and Q₂ are independently a substituted or unsubstitutedquinolinyl or isoquinolinyl group; and n is an integer from 3 to
 10. 24.The compound of claim 23, wherein Q₁ is an 8-quinolinyl group.
 25. Thecompound of claim 23, wherein Q₂ is a 2-quinolinyl group.
 26. Thecompound of claim 25, wherein Q₁ is an 8-quinolinyl group.
 27. Thecompound of claim 26, wherein n is
 5. 28. A compound represented by thefollowing structural formula:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein: R₁ is an arylalkyl: R₂ is a substituted or unsubstituted arylgroup, arylalkyl group, arylamino group, arylalkylamino group, aryloxygroup or arylalkoxy group; A is an amide; and n is an integer from 3 to10.
 29. The compound of claim 28, wherein R₁ is a benzyl group.
 30. Thecompound of claim 29, wherein R₂ is a substituted or unsubstitutedquinolinyl group.
 31. The compound of claim 30, wherein R₂ is anunsubstituted quinolinyl group.
 32. The compound of claim 31, wherein R₂is a 2-quinolinyl group.
 33. The compound of claim 32, wherein n is 5.34. The compound of claim 29, wherein R₂ is a substituted orunsubstituted arylalkyloxy group.
 35. The compound of claim 34, whereinR₂ is a substituted or unsubstituted benzyloxy group.
 36. The compoundof claim 35, wherein R₂ is an unsubstituted benzyloxy group.
 37. Thecompound of claim 36, wherein n is
 5. 38. The compound of claim 29,wherein R₂ is a substituted or unsubstituted phenyl group.
 39. Thecompound of claim 38, wherein R₂ is an unsubstituted phenyl group. 40.The compound of claim 39, wherein n is
 5. 41. The compound of claim 29,wherein R₂ is a substituted or unsubstitued pyridyl group.
 42. Thecompound of claim 41, wherein R₂ is an unsubstituted pyridyl group. 43.The compound of claim 42, wherein R₂ is a β-pyridyl group.
 44. Thecompound of claim 43, wherein n is
 5. 45. A pharmaceutical compositioncomprising a pharmaceutically effective amount of the compound of any ofclaims 1, 18, 23, and 28, and a pharmaceutically acceptable carrier. 46.A method of treating cancer in a subject in need of treatment comprisingadministering to said subject a therapeutically effective amount thecompound of any one of claims 1, 18, 23, and
 28. 47. A method ofselectively inducing terminal differentiation of neoplastic cells andthereby inhibiting proliferation of such cells which comprisescontacting the cells under suitable conditions with an effective amountof the compound of any one of claims 1, 18, 23, and
 28. 48. A method ofselectively inducing cell growth arrest of neoplastic cells and therebyinhibiting proliferation of such cells which comprises contacting thecells under suitable conditions with an effective amount of the compoundof any one of claims 1, 18, 23, and
 28. 49. A method of selectivelyinducing apoptosis of neoplastic cells and thereby inhibitingproliferation of such cells which comprises contacting the cells undersuitable conditions with an effective amount of the compound of any oneof claims 1, 18, 23, and
 28. 50. A method of inducing terminaldifferentiation of tumor cells in a tumor comprising contacting thecells with an effective amount of the compound of any one of claims 1,18, 23, and
 28. 51. A method of inhibiting the activity of histonedeacetylase comprising contacting the histone deacetylase with aneffective amount of the compound of any one of claims 1, 18, 23, and 28so as to inhibit the activity of histone acetylase.
 52. A method oftreating a thioredoxin (TRX)-mediated disease in a subject in needthereof, comprising the step of administering to said subject atherapeutically effective amount of the compound of any one of claims 1,18, 23, and
 28. 53. The method according to claim 52, wherein saidTRX-mediated disease is an inflammatory disease, an allergic disease, anautoimmune disease, a disease associated with oxidative stress or adisease characterized by cellular hyperproliferation.
 54. A method oftreating a disease of the central nervous system in an individual inneed thereof comprising administering to the individual atherapeutically effective amount of the compound of any one of claims 1,18, 23, and
 28. 55. The method according to claim 54, wherein thedisease is a polyglutamine expansion disease.